WO1996002248A1 - Antagonistes des recepteurs des cannabinoides - Google Patents

Antagonistes des recepteurs des cannabinoides Download PDF

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Publication number
WO1996002248A1
WO1996002248A1 PCT/US1995/008455 US9508455W WO9602248A1 WO 1996002248 A1 WO1996002248 A1 WO 1996002248A1 US 9508455 W US9508455 W US 9508455W WO 9602248 A1 WO9602248 A1 WO 9602248A1
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WO
WIPO (PCT)
Prior art keywords
methoxy
compound
benzo
methoxyphenyl
anandamide
Prior art date
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PCT/US1995/008455
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English (en)
Inventor
Kennan Joseph Fahey
Gary Allen Koppel
George Joseph Cullinan
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Eli Lilly And Company
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Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to AT95925517T priority Critical patent/ATE254456T1/de
Priority to JP8505069A priority patent/JPH10503185A/ja
Priority to DE69532162T priority patent/DE69532162T2/de
Priority to EP95925517A priority patent/EP0766559B1/fr
Priority to AU29622/95A priority patent/AU2962295A/en
Publication of WO1996002248A1 publication Critical patent/WO1996002248A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3

Definitions

  • This invention relates to aryl-benzo[b]thiophene and benzofb]furan compounds which are active antagonists of the CB-1 (cannabinol-1) receptor in the mammalian central nervous system.
  • Cannabinoids are compounds derived from the cannabis sativa plant which is commonly known as marijuana.
  • the most active chemical compound of the naturally ocurring cannabinoids is tetrahydrocannabinol (THC) , particularly (-)- ⁇ -THC. This compound was isolated and identified in the
  • anandamide is a key regulator of functions such as sensory perception, cognition, memory, pain perception, and mood modulation. Since it is very clear in humans what the agonism of the CB-1 receptor does with cannabinoids, it would seem reasonable by the same extrapolation to predict the likely pharmacology of antagonists of the CB-1 receptor would possess.
  • This invention provides a compound of formula
  • R! is C1-C4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;
  • R2 and R ⁇ are each independently C1-C4 alkyl or C1-C4 alkoxy;
  • R 4 is CO, CHOH or CH2
  • R5 is O or S, provided that when R ⁇ is hydroxy, R ⁇ is 0, for use in a method of antagonizing one or more of the actions of anandamide at cannabiniol-1 receptors in a mammal.
  • R 2 and R3 are each individually C1-C alkyl or C3.-C4 alkoxy;
  • R 4 is carbonyl; and R ⁇ is oxygen or sulfur.
  • the invention also provides pharmaceutical formulations which include a novel compound of formula (I) as active ingredient in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • Ci ⁇ C4 alkyl represents a straight or branched alkyl chain having from one to four carbon atoms.
  • Typical straight or branched C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.
  • C 1 -C 4 alkoxy represents an oxygen atom connected directly to the C 1 -C 4 alkyl group to form an ether moiety.
  • Examples of C 1 -C 4 alkoxy groups include methoxy, ethoxy, propoxy and butoxy.
  • R! is preferably methoxy, trifluoromethylsulfonyloxy, hydroxy or cyano. Most preferably R ⁇ is cyano.
  • R 2 is preferably methyl or methoxy.
  • R3 is preferably methoxy.
  • R 4 is preferably carbonyl.
  • R5 is preferably -0-.
  • Particularly preferred compounds are those in which R 1 is cyano, R 2 is methoxy, R ⁇ is methoxy, R 4 is carbonyl and R 5 is 0; or R 2 is methyl, R ⁇ is methoxy, R 4 is carbonyl and R 5 is 0; or R 2 is methoxy, R3 is methoxy, R 4 is carbonyl and R ⁇ is S.
  • the compounds of formula I belong to two related chemical groups, the benzothiophene group and the benzofuran group. 1. Benzothiophene Group
  • This group of compounds includes all of the compounds where R 5 is S, shown below:
  • R!-R 4 are as defined above.
  • the most preferred compound has the R 1 group is CN; methoxy groups at R 2 and R 3 ; and R 4 is carbonyl. This substitution defines the most preferred compound, [6- methoxy-2- (4-methoxyphenyl)benzo(b) hien-3-yl] [4-cyanophenyl] methanone which has the following structure:
  • Cyclization of this intermediate to the desired benzo(b) thiophene backbone is achieved by reacting with polyphosphoric acid at elevated temperatures. As shown, the 4-methoxyphenyl moiety tends to arrange via cationic rearrangement to the 2-position of the benzothiophene.
  • the 2-aryl-benzo (b) thiophene intermediate is then reacted with an aryl acyl halide under Friedel-Crafts conditions.
  • the electrophilic substitution takes place primarily on the three position (C 3 ) of the thiophene ring as shown.
  • the 4-methoxy group is substituted by a cyano or nitrile group, which requires the presence of more catalyst due to low electrophility.
  • This intermediate is then oxidized to produce the [6-methoxy-2- (4-methoxyphenyl) -benzo[b] furan-3-yl] -3- (4- methoxyphenyDmethanone intermediate which is well-known in the art.
  • This intermediate is then dealkylated by a well-known procedure to form the 4-hydroxy intermediate shown.
  • a two- step process is then employed to convert the 4-hydroxy moiety to a nitrile group as shown above. First the hydroxy group is converted to a triflate ester derivative and then this compound is reacted with a cyanide source in the presence of a catalyst to complete the conversion to the preferred compound.
  • benzo[b]furan compounds can be synthesized via Friedel-Crafts acylation of the benzo[b]furan intermediate as outlined generally in Scheme IV below, and defined in detail in the specific Examples.
  • Example 4 intermediate A solution of 1.15 grams (3.07 mmol) of the Example 4 intermediate was dissolved in 40 mL. of methylene chloride with .92 mL. of tri-ethyl amine (6.61 mmol) . To this was added a solution of 1.15 g of triflimide (3.23 mmol) in 10 mL. methylene chloride over 15 minutes. After addition, the mixture was allowed to stir at room temperature for 48 hours. The mixture was then diluted with 100 mL methylene chloride, washed twice with 1& H2SO4, twice with deionized water, twice with saturated NaHC03 , then once more with water. Dry on Na2S ⁇ 4 to yield 1.4 grams (89.7%) of the title compound yellow amorphous material.
  • a solution was prepared of 3g (7.7 mmol) of [6-methoxy- 2- (4-methoxyphenyl)benzo[b]thien-3-yl] [4- hydroxyphenyl]methanone in 100 mL of methylene chloride and 1.57g (15.5 mmol) of triethylamine.
  • a solution of 2.8g (7.72 mmol) of triflimide in 50 mL of methylene chloride was slowly added to the reaction mixture over a period of 30 minutes. The reaction, under an atmoshere of nitogen and at room temperature, was allowed to proceed for 16 hours.
  • reaction mixture was washed with 100 mL of 1 N H2SO4, then three times with 100 mL portions of 2N NaOH and finally with 100 mL of water.
  • the organic layer was dried with anhydrous a2S ⁇ 4 and the product allowed to crystallize out. This yielded 2.5 g of the title compound as a yellow solid.
  • a suspension of 2g (3.83 mmol) of the compound of example 7 was prepared in 5 mL of anhydrous acetonitrile with 274 mg (4.21 mmol) of KCN, 125 mg (0.19 mmol) of nickel triphenylphosphine dichloride, 101 mg (0.38 mmol) of triphenylphosphine, and 38 mg (0.58 mmol) of zinc dust.
  • the reaction mixture was heated to 65° C for 90 minutes under a nitrogen atmoshere.
  • the reaction mixture was allowed to cool to room temperature and was diluted with 100 mL of methylene chloride.
  • the reaction mixture was filtered and washed twice with 150 mL portions of water.
  • the organic layer was dried with anhydrous Na2S ⁇ 4.
  • the crude product was recrystallized twice from MeOH. This yielded l.lg of the title compound as a yellow powder.
  • the title compound was prepared in a manner similar to that used in example 3 , by using p-anisoyl chloride as the acylating agent .
  • compositions of the present invention are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing for example up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium sterate and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • compositions of the inventions may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 500 mg, more preferably about 25 to about 300 mg of the active ingredient.
  • the most preferred unit dosage form contains about 10 to about 200 mg of the active ingredient.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • the following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way. For ulation 1
  • Hard gelatin capsules are prepared using the following ingredients:
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • a tablet is prepared using the ingredients below:
  • An aerosol solution is prepared containing the following components:
  • the active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
  • Formulation 4 Tablets each containing 60 mg of active ingredient are made as follows:
  • the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg medicament are made as follows:
  • the active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.
  • Suppositories each containing 225 mg of active ingredient may be made as follows:
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • An intravenous formulation may be prepared as follows:
  • the formula I compounds of the present invention are believed to possess the ability to treat a variety of disorders in mammals, including humans which are associated with cannabinoid stimulation. Such disorders include, without limitation, depression, cognitive dysfunction, loss of memory and poor alertness and sensory perception.
  • the formula I compounds act as antagonists of the cannabinoid receptors. Experiments were performed to demonstrate the antagonist activity of the formula I compounds at the cannabinoid receptors.
  • CHO Chinese hamster ovary cells
  • murine Ltk cells were obtained from The American Type Culture Collection (Rockville, MD) .
  • CHO cells were maintained m an atmosphere of 5% CO 2 m growth media consisting of Alpha-MEM substituted with 10% fetal calf serum, L-glutamme (2mM) and penicillin (50 U/ml) and streptomycin (50 ug/ml) .
  • Ltk cells were cultured at 37'C, in 5% CO 2 in Dulbecco' s modified essential medium (0.45% glucose) containing fetal bovine serum (10%), L-glutamine (2 mM) , penicillin (50 U/ml) and streptomycin (50 ug/ml) .
  • the rat cannabinoid receptor cDNA was stably expressed in CHO cells.
  • a 2.2 kilobase (kb) Sstl-EcoRl fragment containing the complete coding region of the human cannabinoid receptor gene was subcloned into the Sstl and EcoRl sites of the pCD-PS vector to created plasmid hSKR6pl which was transfected into CHO cells using calcium phosphate precipitation.
  • Receptor-containing plasmids were co- transfected with plasmids containing the neomycin resistance gene created in a similar fashion. After transfection, the cells were selected with neomycin and the individual neomycin resistant colonies grown to establish cell lines.
  • the human cannabinoid (CB-1) cDNA was stably expressed in L cells with the following construct designed to amplify receptor expression levels thereby reducing the number of cells required for radioligand binding analysis.
  • a 2.2 kilobase (kb) Sstl-EcoRl fragment containing the complete coding region of the human cannabinoid receptor gene was subclones into the Sstl and EcoRl sites of the pCD-PS vector to create plasmid hSKR6pl. From hSKR ⁇ pl, a 3.3 kb Sall-Ndel fragment was removed, the ends blunted, and inserted into the blunted Sail site of the plasmid ptkmuARS-4.
  • the resulting plasmid contained the receptor gene coding sequence flanked by the SV40 early region promoter and polyadenylation sequence originally engineered into the cloning vector pCD.
  • This plasmid was transfected into murine Ltk cells by calcium phosphate precipitation. After transfection, L cells were selected in HAT medium. Individual HAT-resistant colonies were isolated after 3-4 weeks, grown to established cell lines, and cultured for at least 3 months to allow for expression of the receptor to stabilize.
  • Ltk Cells grown to confluency in 175 cm 2 culture flasks, were washed once with cold phosphate buffered saline and scraped in assay buffer (50 mM Tris, 5 mM EDTA, 5 mg/mL BSA, pH 7.4) with added 200 mM sucrose. Cells were then centrifuged at 1000 X g for 10 minutes at 4' C. The supernatant was discarded and the pellet resuspended in ice cold assay buffer, homogenized with a Tekmar Tissumizer (Cincinnati, OH, USA) at 95% maximal speed for 30 seconds followed by centrifugation for 15 minutes, 2-4 * at 2000 X g.
  • assay buffer 50 mM Tris, 5 mM EDTA, 5 mg/mL BSA, pH 7.4
  • Protein concentrations were determined using the biomchoninic acid protein reagent (Pierce, Rockford, IL) , as described. Binding data were analyzed with the program LIGAND or with program GraphPad (GraphPad Software, San Diego, CA) , which performs weighted nonlinear least squares curve-fitting to the general model of Feldman.
  • Example 15 25800 nM
  • Example 16 5300 nM
  • Example 4 4120 nM
  • Example 7 3600 nM
  • Example 12 1540 nM
  • Example 8 950 nM
  • Example 5 490 nM
  • Example 13 430 nM
  • Example 3 134 nM
  • Example 6 170 nM
  • This assay is to be demonstrate the effect of CB-1 binding compound on the CB-1 signal tranduction pathway, i.e., to establish if the binding compound is working as an agonist or antagonist in vitro.
  • CHO cells were preincubated in growth media with forskolin (10 ⁇ 6 M) with or without anandamide for 4 hours Cyclic AMP accumulation was measured over 5 minutes after exchanging the growth media with serum free media containing forskolin (10 ⁇ 6 M) and anandamide, with or without antagonists as indicated. Data are the mean ⁇ S . E. of three experiments performed in triplicate. The results for the compound of Example 6 are shown in Table 2. In this assay forskolin (FSK) raises the level of cAMP above the basal level (BSD .
  • anadamide inhibits the increase of cAMP induced by the forskolin.
  • the compound of Example 6 inhibits the biological; action of anandamide, i.e., negates the decrease in cAMP caused by anandamide, with an IC50 of approximately 500nM.
  • DMEM was obtained from Biowhittaker and GIBCO, FBS from HyClone, bovine serum albumin (fatty-acid free) , dimethyl- sulfoxide, and NEM from Sigma, PTX from List, ⁇ -CgTX from
  • N18 (neuroblastoma cell line) cells (passages 32-41) were grown on glass coverslip fragments in DMEM plus 5% (fetal bovine serum) (FBS, using standard cell culture techniques. Six to 14 days before recording, cells were "differentiated” by changing the medium to DMEM plus 0.5% FBS plus 2% dimethylsulfoxide. In PTX (Pertussis Toxin) experiments, differentiated cells were grown for an additional 16-20 hours in medium containing 500 ng/ml PTX. Control cells were treated identically, except that neurons were provided by M. S. Shapiro (University of Washington, Seattle, WA) .
  • Tetrodotoxin 200 nM was added to block voltage-gated sodium currents, and bovine serum albumin (3 ⁇ M) was present in all recording solutions to decrease adsorption of cannabinoids.
  • bovine serum albumin 3 ⁇ M was present in all recording solutions to decrease adsorption of cannabinoids.
  • the cannabinoid agonist WIN 55,212 and the compounds of this invention were added.
  • Ic a was measured near the end of a 25-msec depolarizing pulse to 0 mV and was defined as that component of the current sensitive to 100 ⁇ M CdCl 2 - Solution reservoirs were selected by means of a series of solenoid valves, and solution changes were accomplished in ⁇ 1 min. in all experiments the cells were held under voltage clamp at a holding potential of -65 mV.
  • the Open Field Assay evaluates the motion (both horizonal and vertical) of a mouse when placed in a large, open area. Specifically, C57BL/6J mice are injected with 20mg/kg (i.p.) of the compound of Example 6, 28 minutes before injecting anandamide at 2 mg/kg (i.p.). The mouse is placed in the center of a large area of a device which measues the number of vertical and horizontal movements of the mouse (Digiscan Automated Open Field) . Each test session is of 5 minute duration. At the end of this time period, the mouse is removed from the scanner and the recorded data are automatically analyzed and satisically evaluated. Further details are given in Crawley, J. , J. Neurosci., 12(9), p. 3380-3391 (1992).
  • the compounds of formula I have been shown to bind to the human CB-1 receptor and to inhibit the cellular, signal- transduction events evoked by both anandamide and cannabinoids. In vivo, the compounds have been shown to mitigate the effects of anandamide in the mouse. Due to the localization of the CB-1 receptor in the hipocampus and the known pharmacology of the cannabinoids and their correspondence with anandamide (see: Howlett, A.C., et al., TINS, 13(10),p. 420-423.(1990)), mammals, including humans, suffering from symptomology similar to that seen with cannibinoids, would recieve benefit from an antagonist of the CB-1 receptor ( a compound of formula I) .
  • Symptoms which would be benecially effected in mammals, including humans, with a compound of formula I, would include, but not be limited to: depression, loss of cognitive function, loss of mental alertness, loss of memory, and loss of sensory perception. These symptoms occur in a variety of pathological states, syndromes, and diseases. The extent, magnitude, particulars of these symptoms vary widely both between disease states and between various individuals suffering from one of those diseases.

Abstract

On décrit dans la présente demande de brevet certains composés arylbenzo[b]thiophène et benzo[b]furane qui bloquent ou inhibent les récepteurs des cannabinoïdes chez les mammifères. On décrit également de nouveaux composés qui sont des antagonistes des récepteurs des cannabinoïdes, ainsi que des formulations pharmaceutiques contenant ces composés.
PCT/US1995/008455 1994-07-15 1995-07-06 Antagonistes des recepteurs des cannabinoides WO1996002248A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AT95925517T ATE254456T1 (de) 1994-07-15 1995-07-06 Cannabinoid-rezeptor-antagonisten
JP8505069A JPH10503185A (ja) 1994-07-15 1995-07-06 カンナビノイドリセプターアンタゴニスト
DE69532162T DE69532162T2 (de) 1994-07-15 1995-07-06 Cannabinoid-rezeptor-antagonisten
EP95925517A EP0766559B1 (fr) 1994-07-15 1995-07-06 Antagonistes des recepteurs des cannabinoides
AU29622/95A AU2962295A (en) 1994-07-15 1995-07-06 Cannabinoid receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27589594A 1994-07-15 1994-07-15
US08/275,895 1994-07-15

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WO1996002248A1 true WO1996002248A1 (fr) 1996-02-01

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US (2) US5596106A (fr)
EP (1) EP0766559B1 (fr)
JP (1) JPH10503185A (fr)
AT (1) ATE254456T1 (fr)
AU (1) AU2962295A (fr)
CA (1) CA2194684A1 (fr)
DE (1) DE69532162T2 (fr)
ES (1) ES2210301T3 (fr)
WO (1) WO1996002248A1 (fr)

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US5981570A (en) * 1996-09-27 1999-11-09 Eli Lilly And Company Benzothiophene compounds, compositions, and methods
FR2799124A1 (fr) * 1999-10-01 2001-04-06 Sanofi Synthelabo Utilisation des antagonistes des recepteurs aux cannabinoides centraux pour la preparation de medicaments
WO2003061699A1 (fr) * 2001-12-27 2003-07-31 Japan Tobacco, Inc. Remedes pour affections allergiques
US6809085B1 (en) * 1999-05-20 2004-10-26 Chitogenics, Inc. Adherent N,O-Carboxymethylchitosan drug delivery devices for moist tissue and methods of their use
US6825209B2 (en) 2002-04-15 2004-11-30 Research Triangle Institute Compounds having unique CB1 receptor binding selectivity and methods for their production and use
WO2005000301A1 (fr) * 2003-06-20 2005-01-06 F. Hoffmann-La Roche Ag 2-aminobenzothiazoles utilises comme agonistes inverses du recepteur cb1
WO2005023232A2 (fr) * 2003-09-04 2005-03-17 Affibody Ab Nouvelle utilisation et nouveaux procedes associes
US6932971B2 (en) 2002-07-18 2005-08-23 Cytos Biotechnology Ag Hapten-carrier conjugates and uses thereof
US7037944B2 (en) 2000-10-04 2006-05-02 Aventis Pharma S.A. Combination of a CB1 receptor antagonist and of sibutramine, the pharmaceutical compositions comprising them and their use in the treatment of obesity
US7091216B2 (en) 2002-08-02 2006-08-15 Merck & Co., Inc. Substituted furo[2,3-b]pyridine derivatives
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US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7144890B2 (en) 2004-01-28 2006-12-05 Hoffman-La Roche Inc. Spiro-pentacyclic compounds
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7220743B2 (en) 2004-11-09 2007-05-22 Hoffmann-La Roche Inc. Heterocyclic CB1 receptor antagonists
US7229999B2 (en) 2005-04-06 2007-06-12 Hoffmann-La Roche Inc. Pyridine-3-carboxamide derivatives as CB1 inverse agonists
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US5596106A (en) 1997-01-21
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ATE254456T1 (de) 2003-12-15
JPH10503185A (ja) 1998-03-24
CA2194684A1 (fr) 1996-02-01
EP0766559B1 (fr) 2003-11-19
DE69532162D1 (de) 2003-12-24
US5747524A (en) 1998-05-05
DE69532162T2 (de) 2004-09-02
EP0766559A1 (fr) 1997-04-09

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